Institution Williams College Address Department of Biology Williamstown, MA 01267 Principal Investigator Steven J. Swoap Title - AREA: Rapamycin, ambient temperature, and longevity in mice Until recently, additives to the diet have been unable to mimic the lifespan-extension effects of caloric restriction. However, it was very recently shown that the addition of rapamycin, an immunosuppressant drug, to the diet of outbred mice substantially extended their lifespan. The target of rapamycin, called TOR, has been well characterized and is intimately involved with regulation of growth and energy balance - both expenditure and hunger. Signaling pathways impacted by caloric restriction converge on the same pathways that regulate, and are regulated by, mTOR (the mammalian version of TOR). Most of the lifespan extension consequence of caloric restriction in mice requires a mild cold stress (i.e. a typical housing temperature of 220C). In this proposal, we will test the hypotheses that 1) orally administered rapamycin also requires the same cold stress for maximum lifespan extension, 2) significant metabolic depression, bradycardia, and hypothermia are required for rapamycin's effect on lifespan extension, and 3) despite a normal body weight, mice treated with rapamycin will exhibit similar physiological variables as seen with caloric restriction. We propose to use indirect calorimetry and a telemetry-based heart rate and body temperature detection system to measure these physiological variables in mice at different ambient temperatures while either being calorically restricted or with the addition of rapamycin to the diet. Williams College is a small liberal arts school that has had wonderful success excelling in both education and research endeavors. This reflects the truly supportive nature of the college towards faculty research. The administration offers an extremely beneficial sabbatical policy (every three years), built a $50 million science facility five years ago, provides ample space for labs and animal housing, and offers intramural seed money for grant initiatives (like this one). Part of our mission in the sciences at Williams College is the exposure and successful training of undergraduates. Students regularly assume a significant amount of responsibility with research projects and the laboratory environment often takes on an atmosphere comparable to a graduate school research environment where students are working side-by-side with the faculty to design and conduct sophisticated research. My research program continues to involve undergraduates in mainstream research, exposing them to sophisticated and current technology in an integrative biology approach where testing specific hypotheses drive the research. My proposed project would provide an excellent research experience for students who are likely to go on to productive scientific careers. PUBLIC HEALTH RELEVANCE: The restriction of caloric intake extends the lifespan of most organisms tested. In laboratory mice, caloric restriction has its greatest effect when the mice are housed at typical vivarium temperatures of 20-250C. When mice are housed within their thermal neutral zone and calorically restricted, lifespan extension is greatly diminished. Recently, rapamycin was shown to extend the lifespan of mice housed at ambient temperatures well below their thermal neutral zone. Whether rapamycin requires a cool ambient temperature, as does caloric restriction, to increase lifespan in mice remains to be tested and is one of the primary goals of this proposal. Rapamycin has been shown to have effects on the same biochemical pathways influenced by caloric restriction, but it is not known whether rapamycin can induce the same physiological changes induced by caloric restriction. Hence, understanding the physiological influences of rapamycin on mice is of significant importance if compounds like rapamycin are to be used for its life extension properties in other mammals. The overall goals of this proposal are to test the hypotheses that: 1) the extension of lifespan of mice by rapamycin requires a cool ambient temperature, and 2) the rapamycin-treatment mimics the physiological effects induced by caloric restriction.